The glucocorticoid receptor (GR) is a member of the nuclear hormone receptor family of transcription factors, and a member of the steroid hormone family of transcription factors that when bound to a ligand promotes or suppresses the transcription of genes. Glucocorticoid receptor agonists occur naturally or may be prepared synthetically. Glucocorticoids (GC) which interact with GR are potent anti-inflammatory agents and have been used as such in controlling a wide range of allergic and inflammatory conditions, such as asthma, rheumatoid arthritis, eczema and psoriasis. Glucocorticoids have also been used for their immunosuppressive properties and for their anti-tumor effects.
Glucocorticoids have been applied locally to treat dermatitis, asthma, conjunctivitis, and other ophthalmological disorders.
However the use of glucocorticoids is limited by both topical and systemic side-effects, these effects include skin and muscle atrophy, osteoporosis, diabetes, impaired wound healing, susceptibility to infection, HPA dysfunction, adrenal atrophy, cataracts, peptic ulcers, hypertension, metabolic syndrome, and electrolyte imbalance [Shacke et al., Pharmacology and Therapeutics (2002), vol. 96(1), 23-43].
Side effects are usually more severe after systemic rather than topical application. However, even topical therapy can induce systemic adverse effects, as observed after cutaneous therapy for inflammatory dermatitis and pulmonary therapy for asthma. The side effects occur with different prevalence, in different organs, and after different durations of therapy. The severity ranges from more cosmetic aspects, for example teleangiectasia and hypertrichosis, to serious disabling and even life threatening situations (e.g. gastric hemorrhage). [Shacke et al., Pharmacology and Therapeutics (2002), vol. 96(1), 23-43].
The glucocorticoid receptor is activated by binding of the glucocorticoid hormone cortisol and its synthetic derivatives as well as by non-steroidal agonists. Thus steroid-based and non-steroidal-based glucocorticoid analogues are well known in the art.
WO2008/076048 discloses indazolyl ester and amide derivatives for the treatment of glucocorticoid receptor mediated disorders.
WO2009/142571 discloses phenyl and benzodioxinyl substituted indazoles derivatives as modulators of the glucocorticoid receptor.
WO2009/142569 discloses phenyl and pyridinyl substituted indazoles derivatives as modulators of the glucocorticoid receptor.
There is a continuous need for developing novel non-steroidal glucocorticoid receptor modulators (for example agonists, antagonists, partial agonists or partial antagonists). Particularly, development of non-steroidal glucocorticoids that retain the anti-inflammatory efficacy of glucocorticoids while minimizing the side-effects would be of great benefit to a large number of patients with inflammatory diseases. Development of topical non-steroidal glucocorticoids with high systemic clearance and/or short half-life may provide compounds having reduced side-effects while retaining the topical anti-inflammatory efficacy. For topical use the development of non-steroidal glucocorticoids with reduced photo toxicity would be beneficial.